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Natural Product Piperine Alleviates Experimental Allergic Encephalomyelitis in Mice by Targeting Dihydroorotate Dehydrogenase
  • +9
  • zehui liu,
  • qian hu,
  • wanyan wang,
  • sisi lu,
  • Dang Wu,
  • shuyin ze,
  • Jiacheng He,
  • Ying huang,
  • wuyan chen,
  • Yechun Xu,
  • Weiqiang Lu,
  • Jin Huang
zehui liu
East China University of Science and Technology, School of Pharmacy Shanghai, CN
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qian hu
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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wanyan wang
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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sisi lu
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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Dang Wu
East China University of Science and Technology
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shuyin ze
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
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Jiacheng He
East China Normal University
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Ying huang
Guangdong Institute for Drug Control, Guangzhou, Guangdong, China
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wuyan chen
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China
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Yechun Xu
Shanghai Institute of Materia Medica Chinese Academy of Sciences
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Weiqiang Lu
East China Normal University
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Jin Huang
East China University of Science and Technology
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Abstract

BACKGROUND AND PURPOSE Human dihydroorotate dehydrogenase (DHODH) represents a promising therapeutic target for chronic inflammatory and autoimmune diseases. The aim of this study was to discover novel DHODH inhibitor and evaluate the potential of DHODH inhibition in treating multiple sclerosis (MS), a popular chronic inflammatory disease of the central nervous system. EXPERIMENTAL APPROACH Biochemical and Biophysical methods, including enzymatic kinetic analysis, thermofluor assay, isothermal titration calorimetry and X-ray crystallography were used to assess DHODH inhibition. The immunomodulatory activity was assessed by using concanavalin a-triggered T-cell assay and mixed lymphocyte reaction assay. MOG-induced experimental allergic encephalomyelitis (EAE) was used to assess the in vivo therapeutic effects. Myelin destruction and blood–brain barrier (BBB) was evaluated via in vivo imaging KEY RESULTS Piperine was identified as a natural inhibitor of human DHODH with an IC50 value of 0.88 ± 0.04 μM. In addition, we resolved the co-complex crystal structure of DHODH and piperine at 1.98 Å resolution and found that Tyr356 residue of DHODH is critical for piperine binding. Moreover, piperine can markedly suppress T cell overactivation via a DHODH dependent-manner. Finally, we found that piperine exhibits strong preventive and therapeutic effect in the MOG-induced EAE by restricting inflammatory cells infiltration into the CNS and by preventing myelin destruction and blood–brain barrier (BBB) disruption. CONCLUSION AND IMPLICATIONS Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel pharmacological role for piperine in the treatment of MS.